Viral infections are a major threat to public health. The emergence and expansion of life-threatening diseases caused by viruses, together with unmet conventional prevention approaches highlights the necessity of exploring new strategies that target these deadly pathogens.
The soluble protein Gas6 can facilitate viral entry by bridging viral envelope phosphatidylserine to Axl, a receptor tyrosine kinase expressed on target cells. The interaction between phosphatidylserine, Gas6, and Axl was originally shown to be a molecular mechanism through which phagocytes recognize phosphatidylserine exposed on dead cells. Axl/Gas6, as well as other phosphatidylserine receptors, facilitate entry of dengue, West Nile, and Ebola viruses. Virus binding by viral envelope phosphatidylserine is a viral entry mechanism generalized to many families of viruses.
The N-terminal domain of Gas6 binds to PtdSer, a lipid exposed on the viral envelope, and the C-terminal domain binds to Axl, a receptor tyrosine kinase expressed on phagocytic cells. This divalent binding activity enables Gas6 to bridge virus to cells, thereby increasing viral transduction to a level comparable to that for virions bearing wild-type Envs. Gas6 increased the infectious titers of lentiviral vectors pseudotyped with Envs from Sindbis virus (Sindbis), Ross River virus (RRV), and baculovirus (gp64). Gas6 and Axl mediate PtdSer-dependent entry of vaccinia virus. Dengue, West Nile, and Ebola viruses can use the same viral entry pathway.
The receptor tyrosine kinase AXL (also known as Ufo and Tyro7) belongs to a family of tyrosine receptors that includes Tyro3 (Sky) and Mer (Tyro12). A common ligand for AXL family is GAS6 (Growth arrest-specific protein 6). Human AXL is a 2,682-bp open reading frame capable of directing the synthesis of an 894-amino acid polypeptide. Two variant mRNAs have been characterized, transcript variant 1 may be accessed at Genbank, NM_021913.3 and transcript variant 2 may be accessed at NM_001699.4. The polypeptide sequence of the native protein is provided as SEQ ID NO:1, and specific reference may be made to the sequence with respect to amino acid modifications. Important cellular functions of GAS6/AXL include cell adhesion, migration, phagocytosis, and inhibition of apoptosis. GAS6 and AXL family receptors are highly regulated in a tissue and disease specific manner.
AXL is characterized by a unique molecular structure, in that the intracellular region has the typical structure of a receptor tyrosine kinase and the extracellular domain contains fibronectin III and Ig motifs similar to cadherin-type adhesion molecules. During development, AXL is expressed in various organs, including the brain, suggesting that this RTK is involved in mesenchymal and neural development. In the adult, AXL expression is low but returns to high expression levels in a variety of tumors. GAS6 is, so far, the single, activating ligand for AXL.
Antiviral compositions are of great clinical and humanitarian interest.